Project Summary/Abstract Decision-making under uncertainty is a fundamental behavior that is integral to animal health and well-being, and impairments in decision-making are seen in a variety of psychiatric disorders, including depression, anxiety, and substance abuse disorders. Accordingly, understanding the neural mechanisms underlying decision making under uncertainty may provide insights into the mechanisms underlying behavioral disturbances in many psychiatric disorders. Theoretical work strongly suggests that neuromodulatory systems, particularly the locus coeruleus-norepinephrine (LC-NE) system, play an important role in these decision processes5,6, yet predictions of this work at the neural level remain largely untested. The proposed work will directly test predictions of one theory, the adaptive gain theory (AGT), which predicts that the LC-NE system regulates which behavioral strategy is best suited for the current state of the environment: exploiting available rewards or searching for better alternatives. To test this hypothesis, I developed a patch foraging task for rats in operant conditioning chambers. In this task, rats must repeatedly make decisions to harvest reward from a patch, which depletes with each harvest, or to incur a time delay to travel to a new, full patch. AGT predicts that when large rewards are available upon entering a full patch, LC-NE neurons will exhibit phasic burst responses that facilitate decisions to exploit the reward in a patch (harvest from the patch). As the reward within a patch depletes, LC phasic responses will diminish and tonic or baseline firing will increase, facilitating decisions to search for an alternative reward (travel to a new patch). To test these predictions, in Specific Aim 1, single unit recordings of LC-NE neurons will be used to examine whether LC-NE activity conforms to the predictions of AGT described above. In Specific Aim 2, optogenetic manipulations will be used to examine whether LC-NE neurons exert a causal influence on foraging decisions. The proposed research will provide the first direct test of the AGT, promising to improve our understanding of the function of the LC-NE system and our understanding of mechanisms underlying decision-making.